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Multiple dose regimens are frequently required to optimize therapy; however, such therapy is frequently undermined by poor patient adherence. In fact, patient adherence is inversely related to the number of doses a patient is asked to take each drug. Consequently, great efforts are under way to develop drug delivery systems that are able to release drugs over an extended time interval; this could offer considerable benefits including reducing administration frequency. This dissertation describes multiple dose platforms designed to deliver a variety of drugs as a single oral administration are described in this dissertation. We believe these drug delivery systems can be used to enhance patient compliance and achieve better therapeutic outcomes. We developed and tested a novel gastroretentive pulsatile drug delivery platform. This platform could deliver multiple unit doses of a drug in a pulsatile pattern and be controlled by dissolution/erosion of a lag-time interval layer. The platform was designed to be retained in the stomach whilst pulsing drug at various timed intervals. This would allow each dose of the drug to release above or within an optimized absorption window over an extended period of time. To assure the robustness and reproducibility of the platform, various in vitro dissolution studies and physical stability tests were performed and evaluated through drug release characteristics, buoyancy, and structural integrity evaluations. The applicability of the novel multiple dose platform was demonstrated by providing repeated release profiles of ciprofloxacin and verapamil in a single, once-daily delivery system. Ultimately, this dissertation demonstrates that a novel multiple dose platform could be a suitable alternative dosing strategy for a variety of drugs to improve patient adherence and treatment efficacy. / text

Existing models describing the dynamic behavior of a six-pulse rectifier during a short-circuit fault condition are derived from switch models using time-domain average value parametric functions. Unlike these models, novel non-parametric dynamic models have been developed using analytical average-value modeling approach in this work. In this modeling approach, depending upon the number of switches conducting during a switching cycle, the operating point of the rectifier is brought into one of three modes of operation of a six-pulse rectifier. The model for each mode is represented by a differential equation. During output current calculation for the rectifier the operating model is selected based on firing angle and overlap angle functions derived in this paper. They completely characterize the dynamic behavior of current flowing through the dc inductor for a wide range of operating conditions with the exception of harmonics and asymmetrical currents which are dominant for faults occurring at the terminals of the rectifier upstream of the smoothing inductor. The results from the average value model and few other simple models have been applied for Thevenin ac source and synchronous generator supplied rectifier models to determine the characteristics of short circuit current from the rectifier. / text

While geophysical reservoir characterization has been an area of research for the last three decades, geophysical reservoir monitoring, time-lapse studies, have recently become an important geophysical application. Generally speaking, the main target is to detect, estimate, and discriminate the changes in subsurface rock properties due to production. This research develops various sensitivity and feasibility analyses to investigate the effects of production-induced time-lapse changes on geophysical measurements including seismic and controlled-source electromagnetic (CSEM) data. For doing so, a realistic reservoir model is numerically simulated based on a prograding near-shore sandstone reservoir. To account for the spatial distribution of petrophysical properties, an effective porosity model is first simulated by Gaussian geostatistics. Dispersed clay and dual water models are then efficiently combined with other well-known theoretical and experimental petrophysical correlations to consistently simulate reservoir model parameters. Next, the constructed reservoir model is subjected to numerical simulation of multi-phase fluid flow to replicate a waterflooding scenario of a black oil reservoir and to predict the spatial distributions of fluid pressure and saturation. A modified Archie’s equation for shaly sandstones is utilized to simulate rock resistivity. Finally, a geologically consistent stress-sensitive rock physics model, combined with the modified Gassmann theory for shaly sandstones, is utilized to simulate seismic elastic parameters. As a result, the comprehensive petro-electro-elastic model developed in this dissertation can be efficiently utilized in sensitivity and feasibility analyses of seismic/CSEM data with respect to petrophysical properties and, ultimately, applied to reservoir characterization and monitoring research. Using the resistivity models, a base and two monitor time-lapse CSEM surveys are simulated via accurate numerical algorithms. 2.5D CSEM modeling demonstrates that a detectable time-lapse signal after 5 years and a strong time-lapse signal after 10 years of waterflooding are attainable with the careful application of currently available CSEM technology. To simulate seismic waves, I employ different seismic modeling algorithms, one-dimensional (1D) acoustic and elastic ray tracing, 1D full elastic reflectivity, 2D split-step Fourier plane-wave (SFPW), and 2D stagger grid explicit finite difference (FD). My analyses demonstrate that acoustic modeling of an elastic medium is a good approximation up to ray parameter (p) equal to 0.2 sec/km. However, at p=0.3 sec/km, differences between elastic and acoustic wave propagation is the more dominant effect compared to internal multiples. Here, converted waves are also generated with significant amplitudes compared to primaries and internal multiples. I also show that time-lapse modeling of the reservoir using SFPW approach is very fast compared to FD, 100 times faster for my case here. It is capable of handling higher frequencies than FD. It provides an accurate image of the waterflooding process comparable to FD. Consequently, it is a powerful alternative for time-lapse seismic modeling. I conclude that both seismic and CSEM data have adequate but different sensitivities to changes in reservoir properties and therefore have the potential to quantitatively map production-induced time-lapse changes. / text

Formulation intervention, through the application of processing technologies, is a requirement for enabling therapy for the vast majority of drugs. Without these enabling technologies, poorly soluble drugs may not achieve therapeutic concentrations in the blood or tissue of interest. Conversely, freely soluble and/or rapidly cleared drugs may require frequent dosing resulting in highly cyclic tissue concentrations. During the last several years, thermal processing techniques, such as melt mixing, spray congealing, sintering, and hot-melt extrusion (HME), have evolved rapidly. Several new technologies, specifically dry powder coating, injection molding, and KinetiSol® dispersing (KSD), have been adapted to the pharmaceutical arena. Co-rotating twin screw extrusion is routinely applied for the purposes of dissolving poorly soluble drugs into glassy polymers to prepare amorphous solid dispersions, which create supersaturated drug concentrations in the gastro-intestinal tract. A potentially more advantageous alternate geometry, counter-rotating twin screw extrusion was evaluated for preparation of model amorphous solid dispersion and was observed to be more efficient in forming a solid solution and reduced the thermal stress on the drug. HME and KSD processes were utilized to prepare two phase systems consisting of a lipid, glyceryl behenate, and a polymeric amorphous solid dispersion intended to provide both controlled release of drug and supersaturated drug concentrations in the release medium. Such systems are challenging due to the potential for crystallization of the drug within the dosage form during release, which was observed to be influenced by lipophilicity and porosity of the formulation, as well as the surface area to volume ratio of the system. High molecular weight cellulose based glassy dispersions were prepared using a weakly basic model drug by KSD, which when formulated into tablets were optimized to provide either immediate or approximately 2 hours of controlled release under the pH conditions simulating the environment of the stomach. Without formulation intervention in the external phase of the tablet, these compositions gel, muting drug release and missing the drug absorption window. Compositions optimized by an in vitro dissolution test were compared to a lower molecular weight HME prepared commercial product in a beagle dog model and observed to have statistically similar bioavailability, and in one case improved variability. A modified twin screw extrusion machine was utilized to develop a continuous granulation process capable of producing granules that do not require subsequent grinding or sizing. This novel process, which employs previously un-reported temperature profiles, produces lipid based granules that when compressed into tablets produce a controlled release of tramadol hydrochloride, which were not susceptible to alcohol induced dose dumping. / text

SEW refers to the stock of affect-related values that an owning family derives from its family business. As a promising theoretical concept, the SEW has been used widely to explain the diverse strategic choices of family firms compared to non-family firms. However, little study has been done to measure SEW directly and to measure the effect of SEW on family firms’ strategic choices.     Within the context of family-owned Hidden Champions, this thesis study replicates the five-dimension model proposed by Berrone et al. in an empirical study to verify the psychometric measurement on the degree of SEW. Furthermore, internationalization has been chosen as an example to demonstrate the effects of SEW on family firms’ strategic choices and outcomes.   This study has verified the reliability and validity of the SEW scale and SEW’s five subscales constructed. Furthermore, the measurement on SEW and its five dimensions has been applied to examine the effects of SEW and its five dimensions on the internationalization of family firms. The findings reveal that SEW has a negative effect on the internationalization of family firms, which is mainly due to the negative effect of Family Control and Influence.

The influence of water soluble and insoluble stabilizing excipients on the physical stability of coated dosage forms was investigated in this study. The effect of the excipients on the thermal and physico-mechanical properties, and water vapor permeability of free films was studied, as was the influence of these excipients on the physical stability and release kinetics of coated pellets. The effect of water-soluble proteins, bovine serum albumin (BSA) and Type B gelatin, on the physical aging of Eudragit[trademark] RS/RL 30 D films was investigated. It was found that ionic interactions occurred above the isoelectric point of BSA and caused unstable films which showed accelerated decreases in drug release rate. The adjustment of the pH of the dispersion below the isoelectric point of BSA resulted in electrostatic repulsive charges that stabilized the drug release rate from coated dosage forms at both ambient and accelerated conditions. The addition of gelatin to the coating dispersion increased the drug release rate due to the formation of gel-domains through which the drug was able to easily diffuse. The influence of silicon dioxide on the stability of Eudragit[trademark] RS/RL 30 D films was investigated. Colloidal grades showed enhanced incorporation in the acrylic matrix; however, unstable films were formed. The addition of silicon dioxide with a larger particle size increased the permeability of the film and stabilization in drug release rate was attributed to constant water vapor permeability values of free films. The influence of ethylcellulose on the physical aging of Eudragit[trademark] NE 30 D coated pellets was studied. The two polymers were found to be substantially immiscible and the drug release rate of coated pellets was constant at both ambient and accelerated conditions which correlated to stabilizations in both the physico-mechanical properties and water vapor permeability of free films. Blending both Eudragit[trademark] NE 30 D and RS 30 D resulted in the formation of coherent films without the need of plasticizer. The two polymers were found to be miscible and both films and coated dosage forms were stable when stored below the glass transition temperature of the polymer blend. When films were stored above this temperature, instabilities occurred as a result of the further coalescence and densification of the polymer blend.

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第18987号 / 工博第4029号 / 新制||工||1620 / 31938 / 京都大学大学院工学研究科材料工学専攻 / (主査)教授 辻 伸泰, 教授 白井 泰治, 教授 松原 英一郎 / 学位規則第4条第1項該当

Thesis (MTech. degree in Pharmaceutical Sciences)--Tshwane University of Technology, 2010. / Investigates the absorption enchancing properties of N-trimethyl chitosan chloride (TMC) and monocaprin (MC), individually and in combination, on the permeability of insulin across the Caco-2 intestinal epothelial cell line.

I developed a system to release multiple growth factors from PEGylated fibrin gels with varying profiles to induce vasculogenesis from embedded human MSCs. Zero-order release can be obtained by conjugating a growth factor with a homobifunctional, amine-reactive, PEG derivative. Growth factors can be entrapped during thrombin-mediated crosslinking and released rapidly. Growth factors with physical affinity for fibrinogen or fibrin can be sequestered within the matrix and released via degradation and/or disassociation. PDGF-BB was loaded via entrapment while TGF-β1 was sequestered through a combination of physical affinity and conjugation. The affinity of TGF-β1 and fibrinogen had never been previously examined or quantified. I aimed to determine the Ka and Kd between TGF-β1 and fibrinogen through a variety of assays. Binding ELISAs were developed for TGF-β1 and fibronectin, a protein associated with fibrin gels, and TGF-β1 and fibrinogen. However, background was high due to insufficient blocking agents. Other assays explored included western blots, surface plasmon resonance, and radiolabeled TGF-β1 with limited success. The affect of TGF-β1 on human MSC differentiation towards vascular cell phenotypes was examined both in 2D and fibrin gels embedded with MSCs. With exposure to TGF-β1, MSC proliferation was significantly inhibited in both 2D and within fibrin gels indicating that loaded TGF-β1 maintained bioactivity for at least 7 days. Gene expression of MSCs exposed to TGF-β1 demonstrated inhibited endothelial cell differentiation and stimulated smooth muscle cell differentiation. However, confocal and light microscopy indicated that endothelial cell differentiation is maintained with TGF-β1 loaded PEGylated fibrin gels. The system developed is highly modular and can be applied to other tissue engineering systems. Furthermore, other growth factors could be incorporated to promote vascular cell differentiation. / text